Non-interventional studies

While phase I-IV clinical studies investigate the effectiveness of a drug in a patient population according to a clinical study protocol, non-interventional studies treat patients in daily clinical practice under real-life conditions.

A distinction is also made between interventional and non-interventional studies in clinical investigations of medical devices.

A non-interventional study is an investigation in which findings from the treatment of patients with medicinal products and/or medical devices are obtained using epidemiological methods, whereby the treatment, including diagnosis and monitoring, does not follow a predetermined trial protocol, but corresponds exclusively to normal medical practice.

Depending on the classification of the investigational medical device, non-interventional studies are regulated differently by law:

• According to Section 4 (23) of the German Medicinal Products Act (AMG): "A non-interventional trial is an investigation in which findings from the treatment of persons with medicinal products are analysed using epidemiological methods; in this context, the treatment, including diagnosis and monitoring, does not follow a predetermined trial protocol, but exclusively follows medical practice; furthermore, insofar as it concerns a medicinal product subject to authorisation or subject to approval pursuant to Section 21a (1), this is carried out in accordance with the instructions for its use specified in the authorisation or approval."
• Art. 74 or 82 of Regulation (EU) 2017/745 (MDR) and Annex XIV
• §Section 15 of the Professional Code of Conduct for Physicians Practising in Germany (BOÄ)
• in Germany as "other clinical investigations" in accordance with Section 3 (4) and the requirements of Section 47 of the Medical Devices Implementation Act (MPDG), which must be read in conjunction with EU MDR 2017/745

Post-marketing surveillance of medicinal products

Post-marketing surveillance studies (PMA) are studies that are intended to gather information on the use of authorised or registered medicinal products. Post-marketing surveillance studies are not interventional trials within the meaning of Section 4 (23) sentence 3 of the German Medicines Act (AMG). AWBs are not subject to authorisation, but are notified. In accordance with Section 67 (6) (10) AMG, the competent higher federal authority makes the notifications and final reports submitted to it available to the public on the Internet.

Regulation (EU) 2017/745 on medical devices (EU MDR 2017/745) also regulates clinical evaluation (Annex XIV, Article 61) via clinical investigations (Annex XIV, Articles 62-82), post-market clinical follow-up (Article 74, post-market clinical follow-up; PMCF, Annex XIV) and post-market surveillance (PMS, Article 83). The clinical evidence for PMCF and PMS can be obtained through observational studies in compliance with the regulations.

Post-authorisation efficacy evaluation of a medicinal product (PAES)

A post-authorisation efficacy study (PAES) is conducted to improve the understanding of the therapeutic effectiveness and benefit-risk of a medicinal product with implications for optimal use in clinical benefit. The design of the study should be ethically and scientifically justified.

The European Medicines Agency (EMA) has developed a scientific guideline that describes how the studies should be designed to support regulatory decision-making in the European Union.

Post-authorisation safety assessment (PASS)

A post-authorisation safety study pursuant to Section 4 (34) of the German Medicinal Products Act (AMG) is defined as follows: "A post-authorisation safety study for a medicinal product intended for human use is any study of an authorised medicinal product conducted to identify, characterise or quantify a safety risk, to confirm the safety profile of a medicinal product or to measure the efficacy of risk management measures."

A post-authorisation safety study can be ordered or voluntarily initiated, financed and conducted by the company.

Non-interventional studies for medical devices

General conditions

The framework conditions for non-interventional clinical studies of medical devices can be found in:

• MDR
• MPDG (German national law)
• DiGAV (Digital Health Applications Ordinance)
• ISO 14155

According to DIN EN ISO 14155:2021-05, I.6.3, non-interventional clinical investigations are a special type of study for medical devices after placing on the market (on the market with CE marking). Further applies:

• The medical device is used as it is normally used.
• Doctors decide which product is most suitable for a patient according to clinical need. There is no predetermined plan that determines who gets which product.
• The decision to use the product has nothing to do with whether someone takes part in the trial or not.
• Patients do not have to undergo any additional or stressful examinations.
• The researchers collect data and analyse it using special methods in order to gain insights into the product.

Such studies are often referred to as "observational studies" because the researchers only observe what happens in normal medical practice anyway, without intervening.

ISO 14155 refers mainly to interventional clinical investigations and less to non-interventional studies.

Elements that show that these are NOT non-interventional (observational) studies for medical devices (exemplary):

• Randomisation (random distribution to treatment or no treatment)
• Use of a medical device without CE marking
• Use of a CE-marked medical device outside its intended purpose
• Examination of whether compliance with an in vitro diagnostic medical device leads to a different medical decision
• Additional invasive or stressful measures

ATTENTION: According to German law (MPDG and §15 of the BOÄ), investigators involved in non-interventional studies are obliged to seek professional and ethical consultation with the ethics committee responsible for them BEFORE starting such a study.

Examples of non-interventional studies for medical devices

Non-interventional studies (NIS) for medical devices:

• These are not explicitly regulated in the MDR, but are mentioned in national law (e.g. in the German MPDG).
• According to the MPDG, NIS are systematic investigations of CE-labelled medical devices within the scope of their intended purpose that do not require any additional invasive or stressful measures.

Post-market clinical follow-up (PMCF) studies:

• These are provided for in the MDR and serve to further evaluate CE-labelled devices within their intended purpose.
• PMCF studies fall under Article 74 (1) MDR and have less stringent requirements than "normal" clinical investigations.

Application observations (AWB):

• These are provided for in German law for medical devices, similar to medicinal products.
• AWBs are used to monitor the use of medical devices under everyday conditions.

Retrospective data analyses:

• These are not considered clinical investigations under MDR or NIS, but fall under the general provisions of research law.

Analyses of patient registries:

• Similar to retrospective data analyses, these are not considered clinical investigations or NIS.

For DiGA manufacturers, non-interventional studies in the sense of a so-called "systematic data evaluation" according to DiGAV (Digital Health Applications Ordinance) can be used for the preliminary inclusion of a DiGA in order to demonstrate the potential of a medical app.

Manufacturers and sponsors should observe the specific national regulations when planning non-interventional studies for medical devices, as the MDR does not provide any standardised requirements here. In addition, it is advisable to contact the competent authorities for consultation if you are unsure about the classification of a study.

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